User:SamSenatore/Upstream and downstream (transduction)

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TGF-β signaling as a demonstration of upstream signaling[edit]

The upstream signaling pathway is triggered by the binding of a signaling molecule, a Ligand, to a receiving molecule, Receptor (biochemistry).  Receptors and ligands exist in many different forms, and they will only recognize/bond particular molecules. Upstream extracellular signaling transduce an endless variety of intracellular cascades. [1] Receptors and ligands are common upstream signaling molecules that dictate the downstream elements of the signal pathway. A plethora of different factors affect which ligands bind to which receptors, and the downstream cellular response that it initiates.

TGF-β[edit]

The extracellular type II and type I kinase receptors binding to the TGF-β ligands.


Transforming growth factor-β (TGF-β) is a superfamily of cytokines that play a significant upstream role in regulating of Morphogenesis, Homeostasis, cell proliferation, and differentiation.[2] The significance of TGF-β is apparent with the human diseases that occur when TGF-β processes are disrupted, such as cancer, and skeletal, intestinal and cardiovascular diseases.[3] [4] TGF-β is pleiotropic and multifunctional, meaning they are able to act on a wide variety of cell types.[5]

Determinants of TGF-β action[edit]

The effects of transforming growth factor-β (TGF-β) are determined by cellular context. There are three kinds of contextual factors that determine the shape the TGF-β response: the signal transduction components, the transcriptional cofactors and the epigenetic state of the cell. The different ligands and receptors of TGF-β are significant as well in the composition signal transduction pathway.[6][2]

Contextual Factors that determines TGF-β response[edit]

Upstream TGF-β Signaling Pathway[edit]

The type II receptors phosphorylate the type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as transcriptional regulators.

Signaling is initiated by the binding of TGF-β to its serine/threonine receptors. The serene/threonine receptors are the type II and type I receptors on the cell membrane.[7][2] Binding of a TGF-β members induces assembly of a heterotetrameric complex of two type I and two type II receptors at the plasma membrane. [8] Individual members of the TGF-β family bind to a certain set of characteristic combination of these type I and type II receptors. [9] The type I receptors can be divided into two groups, which depends on the cytoplasmic R-Smads that they bind and phosphorylate. The first group of type I receptors (Alk1/2/3/6) bind and activate the R-Smads, Smad1/5/8. The second group of type I reactors (Alk4/5/7) act on the R-Smads, Smad2/3. The phosphorylated R-Smads then form complexes and the signals are funneled through two regulatory Smad (R-Smad) channels (Smad1/5/8 or Smad2/3).[8][2] After the ligand-receptor complexes phosphorylate the cytoplasmic R-Smads, the signal is then sent through Smad 1/5/8 or Smad 2/3. This leads to the downstream signal cascade and cellular gene targeting.[5][7]

Downstream TGF-β Signaling Pathway[edit]

TGF-β regulates multiple downstream processes and cellular functions. The pathway is highly variable based on cellular context. TGF-β downstream signaling cascade includes regulation of cell growth, cell proliferation, cell differentiation, and apoptosis. [10]




Referances[edit]

  1. ^ Miller, Daniel S. J.; Schmierer, Bernhard; Hill, Caroline S. (2019-07-15). "TGF-β family ligands exhibit distinct signalling dynamics that are driven by receptor localisation". Journal of Cell Science. 132 (14): jcs234039. doi:10.1242/jcs.234039. ISSN 0021-9533. PMC 6679586. PMID 31217285.{{cite journal}}: CS1 maint: PMC format (link)
  2. ^ a b c d Massagué, Joan (2012-10). "TGFβ signalling in context". Nature Reviews Molecular Cell Biology. 13 (10): 616–630. doi:10.1038/nrm3434. ISSN 1471-0080. PMC 4027049. PMID 22992590. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  3. ^ Kashima, Risa; Hata, Akiko (2018-01-01). "The role of TGF-β superfamily signaling in neurological disorders". Acta Biochimica et Biophysica Sinica. 50 (1): 106–120. doi:10.1093/abbs/gmx124. ISSN 1672-9145. PMC 5846707. PMID 29190314.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ Huang, Tao; Schor, Seth L.; Hinck, Andrew P. (2014-09-16). "Biological Activity Differences between TGF-β1 and TGF-β3 Correlate with Differences in the Rigidity and Arrangement of Their Component Monomers". Biochemistry. 53 (36): 5737–5749. doi:10.1021/bi500647d. ISSN 0006-2960. PMC 4165442. PMID 25153513. {{cite journal}}: line feed character in |title= at position 47 (help)
  5. ^ a b Letterio, John J.; Roberts, Anita B. (1998-04-01). "REGULATION OF IMMUNE RESPONSES BY TGF-β". Annual Review of Immunology. 16 (1): 137–161. doi:10.1146/annurev.immunol.16.1.137. ISSN 0732-0582.
  6. ^ Massagué, Joan (2012-10). "TGFβ signalling in context". Nature Reviews Molecular Cell Biology. 13 (10): 616–630. doi:10.1038/nrm3434. ISSN 1471-0080. PMC 4027049. PMID 22992590. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  7. ^ a b Vilar, Jose M. G.; Jansen, Ronald; Sander, Chris (2006-01-27). "Signal Processing in the TGF-β Superfamily Ligand-Receptor Network". PLOS Computational Biology. 2 (1): e3. doi:10.1371/journal.pcbi.0020003. ISSN 1553-7358. PMC 1356091. PMID 16446785.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  8. ^ a b Vilar, Jose M. G.; Jansen, Ronald; Sander, Chris (2006-01-27). "Signal Processing in the TGF-β Superfamily Ligand-Receptor Network". PLOS Computational Biology. 2 (1): e3. doi:10.1371/journal.pcbi.0020003. ISSN 1553-7358. PMC 1356091. PMID 16446785.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  9. ^ Heldin, Carl-Henrik; Moustakas, Aristidis (2016-08-01). "Signaling Receptors for TGF-β Family Members". Cold Spring Harbor Perspectives in Biology. 8 (8): a022053. doi:10.1101/cshperspect.a022053. ISSN 1943-0264. PMID 27481709.
  10. ^ Shuang, Li Nian; Chuan, Xie; Hua, Lu nong (2015). "Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis". Frontiers in Cellular and Infection Microbiology. 5. doi:10.3389/fcimb.2015.00077. ISSN 2235-2988. PMC 4632021. PMID 26583078.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)


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